Presynaptic plasticity of dopamine release in the cortex and basal ganglia is involved in learning cues that[unreadable] elicit cocaine self-administration and underlie selective attention by filtering non-salient stimuli. The objective[unreadable] of this proposal is to characterize mechanisms that mediate presynaptic plasticity at the level of the[unreadable] dopaminergic synaptic vesicle exocytosis.[unreadable] We recently reported that the fusion pores of small DAergic synaptic vesicles can flicker once or multiple[unreadable] times as fast as 10 kHz, thus regulating the amount of transmitter released from a vesicle. This provides the[unreadable] basis for Aim 1, which asks how flickering of fusion pores is regulated.[unreadable] In chromaffin cells, we discovered that the level of vesicle acidification is not invariant but enhanced by[unreadable] cellular activity, which can increase quantal size. In this proposal, we show evidence for enhanced vesicular[unreadable] acidification that may underlie drug actions (e.g., Ritalin), and a means for behavior to feed back to alter[unreadable] long-term transmission. This provides the basis for Aim 2 explores whether psychostimulants regulate[unreadable] quantal size via rebound of vesicular acidification.[unreadable] Finally, we identified how a variety of presynaptic receptors alter DA transmission at the quantal level[unreadable] (e.g., GDNF, D2, nicotinic, and mGluR activation) and why these factors are important for DA as social[unreadable] synapses. Most of the work has been on acute effects of neurotransmitters. New evidence indicates long-lasting[unreadable] effects of neurotransmitters on DA transmission, particularly on the density/formation of axonal[unreadable] presynaptic varicosities. Accordingly, Aim 3 will examine how neurotransmitters regulate DAergic[unreadable] presynaptic varicosity formation.